Millennium Institute for Cell Dynamics and Biotechnology

Santiago, Chile

Millennium Institute for Cell Dynamics and Biotechnology

Santiago, Chile
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Luhr S.,University of Chile | Vilches-Herrera M.,University of Chile | Fierro A.,University of Santiago de Chile | Fierro A.,Millennium Institute for Cell Dynamics and Biotechnology | And 8 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010

2-Arylthiomorpholine and 2-arylthiomorpholin-5-one derivatives, designed as rigid and/or non-basic phenylethylamine analogues, were evaluated as rat and human monoamine oxidase inhibitors. Molecular docking provided insight into the binding mode of these inhibitors and rationalized their different potencies. Making the phenylethylamine scaffold rigid by fixing the amine chain in an extended six-membered ring conformation increased MAO-B (but not MAO-A) inhibitory activity relative to the more flexible α-methylated derivative. The presence of a basic nitrogen atom is not a prerequisite in either MAO-A or MAO-B. The best Ki values were in the 10-8 M range, with selectivities towards human MAO-B exceeding 2000-fold. © 2010 Elsevier Ltd. All rights reserved.


Rivera-Meza M.,Laboratory of Gene Therapy | Quintanilla M.E.,University of Chile | Tampier L.,University of Chile | Mura C.V.,Millennium Institute for Cell Dynamics and Biotechnology | And 4 more authors.
FASEB Journal | Year: 2010

Humans who carry a point mutation in the gene coding for alcohol dehydrogenase-1B (ADH1B*2; Arg47His) are markedly protected against alcoholism. Although this mutation results in a 100-fold increase in enzyme activity, it has not been reported to cause higher levels of acetaldehyde, a metabolite of ethanol known to deter alcohol intake. Hence, the mechanism by which this mutation confers protection against alcoholism is unknown. To study this protective effect, the wild-type rat cDNA encoding rADH-47Arg was mutated to encode rADH-47His, mimicking the human mutation. The mutated cDNA was incorporated into an adenoviral vector and administered to genetically selected alcohol-preferring rats. The V max of rADH-47His was 6-fold higher (P<0.001) than that of the wild-type rADH-47Arg. Animals transduced with rAdh-47His showed a 90% (P<0.01) increase in liver ADH activity and a 50% reduction (P<0.001) in voluntary ethanol intake. In animals transduced with rAdh-47His, administration of ethanol (1g/kg) produced a short-lived increase of arterial blood acetaldehyde concentration to levels that were 3.5- to 5-fold greater than those in animals transduced with the wild-type rAdh-47Arg vector or with a noncoding vector. This brief increase (burst) in arterial acetaldehyde concentration after ethanol ingestion may constitute the mechanism by which humans carrying the ADH1B*2 allele are protected against alcoholism. © FASEB.


Galdamez A.,University of Chile | Garcia-Beltran O.,Andrés Bello University | Cassels B.K.,University of Chile | Cassels B.K.,Millennium Institute for Cell Dynamics and Biotechnology
Journal of the Chilean Chemical Society | Year: 2011

The crystal structure of ethyl 7-hydroxy-2-oxo-2H-chromene-3-carboxylate monohydrate (1), C12H10O5.H2O, was established by X-ray crystallographic analysis. The molecule of the title compound is essentially planar except for the carboxylate substituent group. The crystal packing supramolecular array arises from hydrogen bonds and intermolecular C-H⋯O=C contacts of the organic molecules and solvent water molecules, with graph-set descriptor)R2 4(8), R 2 1(6), R4 4(20)and5 (C) motifs. The water molecules are involved as donors and acceptors. The hydrogen bond and intermolecular interaction network is reinforced by stacking of the sheet through π-π interactions.


Castro-Castillo V.,Metropolitan University of Educational Sciences | Castro-Castillo V.,University of Chile | Rebolledo-Fuentes M.,University of Chile | Theoduloz C.,University of Talca | And 2 more authors.
Journal of Natural Products | Year: 2010

Lakshminine (6-amino-1-aza-5-methoxy-7H-dibenzo[de,h]quinolin-7-one, 1) is a recent addition to the small family of oxoisoaporphine alkaloids and a member of an even smaller set bearing an amino group at C-6. This rare natural product has now been synthesized in order to have sufficient amounts for biological testing. Lakshminine, its 4-amino isomer (2), their 6- and 4-nitro precursors (8 and 10, respectively), the intermediate 5-methoxy-7H-dibenzo[de,h]quinolin-7- one (6), and the unsubstituted skeleton (11) were tested against normal human fibroblasts and three human solid tumor cell lines. Only compound 10 showed marginal antiproliferative activity. © 2010 The American Chemical Society and American Society of Pharmacognosy.


Perez E.G.,University of Santiago de Chile | Perez E.G.,Millennium Institute for Cell Dynamics and Biotechnology | Cassels B.K.,University of Chile | Cassels B.K.,Millennium Institute for Cell Dynamics and Biotechnology | And 2 more authors.
Bioorganic and Medicinal Chemistry | Year: 2012

In this study thirty-three novel indole derivatives were designed and synthesized based on the structure of deformylflustrabromine B (1), a metabolite isolated from the marine bryozoan Flustra foliacea L. The syntheses were carried out using standard methodologies and in good yields. The molecules were tested for their affinities for the α4β2*, α3β 4*, α7* and (α1)2β1γδ nicotinic acetylcholine receptor (nAChR) subtypes. Binding assays showed that, among these ligands, compound 7c exhibited the highest affinity with K i = 136.1, 93.9 and 862.4 nM for the α4β2*, α3β4*, and α7* nAChRs subtypes, respectively. These results indicated that the indole core might be a useful scaffold for the development of new potent and selective nAChR ligands. © 2012 Elsevier Ltd. All rights reserved.


Pessoa-Mahana H.,University of Chile | Nunez C.U.,University of Chile | Araya-Maturana R.,University of Chile | Barria C.S.,University of Chile | And 10 more authors.
Chemical and Pharmaceutical Bulletin | Year: 2012

A series of 3-[3-(4-aryl-1-piperazinyl)-propyl]-1H-indole derivatives (12a-h) was synthesized and evaluated for binding affinity at the human 5-hydroxytryptamine 1A receptor (5-HT 1AR) compounds (12b) and (12h) showed the highest 5-HT 1A receptor affinity (IC 50-=15 nM). Molecular docking studies with all the compounds in a homology model of 5-HT 1A showed that the main interaction anchoring the ligand in the receptor was a charge-reinforced bond between the protonated nitrogen atom (N-4) of the piperazine ring and Aspartate 3.32. © 2012 The Pharmaceutical Society of Japan.


Ojeda-Gomez C.,University of Chile | Pessoa-Mahana H.,University of Chile | Iturriaga-Vasquez P.,Millennium Institute for Cell Dynamics and Biotechnology | Pessoa-Mahana C.D.,University of Santiago de Chile | And 2 more authors.
Archiv der Pharmazie | Year: 2014

A series of functionalized indolylalkylarenes 3-16(a and b) were synthesized and their affinities for the serotonin transporter were investigated in vitro. Compounds 3-12(a and b) were obtained by nucleophilic substitution of 3-(1H-indol-3-yl)propyl-4-methylbenzenesulfonates 2(a and b) with a series of azaheterocycles. Compounds 14-16(a and b) were prepared in a two-step sequence by reaction of 3-(1H-indol-3-yl)-2-methylpropanal with substituted 1,2-phenylenediamines. Compounds 3b, 4b, and 5b showed good binding affinities (Ki = 33.0, 48.0, and 17 nM, respectively). The other synthesized compounds showed moderate or no affinity in the binding studies. The affinities for the serotonin transporter of a new series of functionalized indolylalkylarenes 3-16(a and b) were investigated in vitro. With Ki values of 33.0, 48.0, and 17 nM, compounds 3b, 4b, and 5b, respectively, showed good binding affinities. The other synthesized compounds showed moderate or no affinity in the binding studies. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Meza R.C.,University of Santiago de Chile | Ortiz F.C.,University of Santiago de Chile | Bravo E.,University of Santiago de Chile | Iturriaga-Vasquez P.,University of Chile | And 3 more authors.
Neurochemistry International | Year: 2012

The carotid bodies (CBs) are chemosensory organs that respond to hypoxemia with transmitter neurosecretion, leading to a respiratory reflex response. It has been proposed that acetylcholine is a key regulator of transmitter release through activation of presynaptic nicotinic acetylcholine receptors (nAChRs). In the present work, we studied the identity of such nAChRs and their contribution to catecholamine release from CBs. Neonatal rat CBs were placed in a recording chamber for electrochemical recordings or disassociated for voltage-clamp studies on isolated cells. Fast nicotine superfusion increases catecholamine release from intact CBs. This response was diminished reversibly by the non-selective nAChR blocker hexamethonium, by the selective α7 blocker α-bungarotoxin and by the α4-containing nAChR blocker erysodine. In isolated CB cells the nAChR agonists nicotine, acetylcholine and cytisine all evoke inward currents with similar potencies. The nicotine-evoked current was fully blocked by mecamylamine and partially inhibited by α-bungarotoxin or erysodine. However, the combination of both α-bungarotoxin an erysodine failed to suppress this response. Immunodetection studies confirm the presence of α7 and α4 subunits in isolated dopaminergic CB cells. Our results show that activation of α7 and/or α4-containing nAChR subtypes have the ability to regulate catecholamine release from intact CB due to activation of fast inward currents expressed in chemoreceptor cells. Therefore, our results suggest that both nAChR subtypes contribute to the cholinergic nicotinic regulation of catecholamine signaling in the carotid body system. © 2011 Elsevier Ltd. All rights reserved.


Perez E.G.,Millennium Institute for Cell Dynamics and Biotechnology | Perez E.G.,University of Santiago de Chile | Mendez-Galvez C.,University of Chile | Cassels B.K.,Millennium Institute for Cell Dynamics and Biotechnology | Cassels B.K.,University of Chile
Natural Product Reports | Year: 2012

This review covers classical and modern structural modifications of the alkaloid, the more recent (since 2007) syntheses of cytisine and analogues, and the pharmacology of these compounds, with emphasis on their interactions with nicotinic receptors. 89 references are cited. © The Royal Society of Chemistry 2012.


PubMed | Millennium Institute for Cell Dynamics and Biotechnology
Type: Journal Article | Journal: Natural product reports | Year: 2012

Covering: up to the end of 2011. This review covers classical and modern structural modifications of the alkaloid, the more recent (since 2007) syntheses of cytisine and analogues, and the pharmacology of these compounds, with emphasis on their interactions with nicotinic receptors. 89 references are cited.

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